Imidazo[2,1-b]thiazoles and their use as pharmaceuticals

ABSTRACT

The present invention relates to derivatives of imidazo[2,1-b]thiazoles of formula I, 
     
       
         
         
             
             
         
       
     
     in which R, R1 to R3 and n have the meanings indicated in the claims, which modulate the transcription of endothelial nitric oxide (NO) synthase and are valuable pharmacologically active compounds. Specifically, the compounds of formula I upregulate the expression of the enzyme endothelial NO synthase and can be applied in conditions in which an increased expression of said enzyme or an increased NO level or the normalization of a decreased NO level is desired. The invention further relates to processes for the preparation of compounds of formula I, to pharmaceutical compositions comprising them, and to the use of compounds of formula I for the manufacture of a medicament for the stimulation of the expression of endothelial NO synthase or for the treatment of various diseases including cardiovascular disorders such as atherosclerosis, thrombosis, coronary artery disease, hypertension and cardiac insufficiency, for example.

The present invention relates to derivatives of imidazo[2,1-b]thiazolesof formula I,

in which R, R1 to R3 and n have the meanings indicated below, whichmodulate the transcription of endothelial nitric oxide (NO) synthase andare valuable pharmacologically active compounds. Specifically, thecompounds of formula I upregulate the expression of the enzymeendothelial NO synthase and can be applied in conditions in which anincreased expression of said enzyme or an increased NO level or thenormalization of a decreased NO level is desired. The invention furtherrelates to processes for the preparation of compounds of formula I, topharmaceutical compositions comprising them, and to the use of compoundsof formula I for the manufacture of a medicament for the stimulation ofthe expression of endothelial NO synthase or for the treatment ofvarious diseases including cardiovascular disorders such asatherosclerosis, thrombosis, coronary artery disease, hypertension andcardiac insufficiency, for example.

Endothelial NO synthase (eNOS, NOS-III) belongs to a group of threeisoenzymes which produce nitric oxide (nitrogen monoxide, NO) byoxidation of arginine. Endothelially released NO is of centralimportance in a number of key cardiovascular mechanisms. It has avasodilating effect and inhibits the aggregation of platelets, theadhesion of leukocytes to the endothelium and the proliferation ofintimal smooth muscle cells.

Endothelial NO synthase is subject to physiological andpathophysiological regulation both at the transcriptional and at thepost-transcriptional level. Enzyme already present in the endotheliummay undergo calcium-dependent and calcium-independent activation throughphosphorylation of specific amino acids, but also by direct interactionswith specific proteins. Stimulators of this, usually transient, NOrelease are extracellular arginine, 17β-estrogen and the mechanicalstimulus exerted on the luminal surface of the endothelium by the bloodflow (shear stress). The latter additionally leads to regulation of eNOSat the transcriptional level. Thus, for example, Sessa et al. (Circ.Research 74 (1994), 349-353) were able to obtain a marked increase ineNOS by means of exercise training and the increase in shear stressassociated therewith.

Whether regulation at the post-transcriptional level is relevant invivo, has not been unambiguously proven. Thus, for example,administration of a high arginine dose is followed by only a transientimprovement in the endothelium-dependent vasorelaxation in patients withcoronary heart disease.

On the other hand, the significance of the upregulation of the eNOSprotein is scientifically accepted. Thus, there are findings which showthat the protective properties of the HMG-CoA reductase inhibitorsimvastatin can be attributed, besides to the lipid lowering, also inpart to an increase in eNOS expression in vivo (Endres et al., Proc.Natl. Acad. Sci. USA 95 (1998), 8880-8885). It is additionally knownthat single point mutations in the 5′-flanking region of the eNOS gene(“eNOS promoter”), and the reduction in the rate of eNOS genetranscription associated therewith, in the Japanese population isassociated with an increase in the risk of coronary spasms (Nakayama etal., Circulation 99 (1999), 2864-2870).

The current assumption therefore is that the transcriptional andpost-transcriptional mechanisms of eNOS regulation are seriouslydisturbed in a large number of disorders, especially in cardiovasculardisorders. Even in very early stages of a wide variety of cardiovasculardisorders it is possible for a dysfunction of this type in theendothelium lining the blood vessels to lead to a deficiency ofbioactive NO, which is manifested as the disorder progresses in the formof measurable pathophysiological and morphological changes. Thus,critical steps in early atherogenesis are speeded up by a decrease inendothelial NO release, such as, for example, the oxidation of lowdensity lipoproteins, the recruitment and deposition of monocytes in theintima of vessels, and the proliferation of intimal cells. A consequenceof atherogenesis is the formation of plaques on the inside of the bloodvessels, which may in turn lead, through a diminution in the shearstress, to a further decrease in endothelial NO release and a furtherdeterioration in the pathology. Since endothelial NO is also avasodilator, a decrease thereof frequently also leads to hypertensionwhich may, as an independent risk factor, cause further organ damage.

The aim of a therapeutic approach to the treatment of these disordersmust accordingly be to interrupt this chain of events by increasing theendothelial NO expression. Gene transfer experiments which lead in vitroto overexpression of NO synthase in previously damaged vessels are infact able to counteract the described processes and are thus evidence ofthe correctness of this approach (Varenne et al., Hum. Gene Ther. 11(2000), 1329-1339).

Some low molecular weight compounds which, in cell cultures, may lead toa direct effect on eNOS transcription and expression are disclosed inthe literature. For the statins, as has already been mentioned, it hasbeen possible to show such an increase in eNOS in vivo as a side effect.In view of the known range of side effects of this class of substances,however, it is unclear how far use of this effect can be made in atoxicologically unproblematic dose. Liao et al. claim in WO 99/47153 andWO 00/03746 the use of rhoGTPase inhibitors and agents which influencethe organization of the actin cytoskeleton for increasing eNOS inendothelial cells and for the therapy of various disorders such as, forexample, strokes or pulmonary hypertension without, however, indicatinga specific way of achieving this. Certain amide derivatives whichupregulate the expression of endothelial NO synthase, in particularN-cycloalkyl amides in which the cycloalkyl ring is fused to a benzenering or a heteroaromatic ring, have been described in WO 02/064146, WO02/064545, WO 02/064546, WO 02/064565, WO 2004/014369, WO 2004/014372and WO 2004/014842. Certain triaza- and tetraaza-anthracenedionederivatives which upregulate the expression of endothelial NO synthasehave been described in WO 2004/094425. There still exists a need forfurther compounds which upregulate the expression of endothelial NOsynthase and have a favorable property profile and are useful aspharmaceuticals for the treatment of various diseases such asatherosclerosis, coronary artery disease or cardiac insufficiency, forexample. Surprisingly it has now been found that the compounds offormula I are modulators of the transcription of endothelial NO synthaseand in particular stimulate, or upregulate, the expression of eNOS, andare useful for the treatment of various diseases such as the mentionedcardiovascular disorders.

Certain compounds which are encompassed by formula I, in which R3 isdefined as (C₁-C₆)-alkoxycarbonyl or COOH, are described in a number ofdocuments including WO 2006/008556, Matsukawa et al., Yakugaku Zasshi 71(1951), 756-759; Pyl et al., Liebigs Ann. Chem. 657 (1962), 113-120; Abeet al., Chemistry Letters (1980), 223-224; Abe et al., Bull. Chem. Soc.Japan 53 (1980), 3308-3312; Abe et al., Bull. Chem. Soc. Japan 55(1982), 200-203; and Abe et al., J. Chem. Research, Synopses (1999),322-323. A stimulating effect of these known compounds of formula I onthe transcription or the expression of eNOS and their use in thetreatment of diseases which is based on such effect, has not yet beendescribed.

A subject of the present invention is the use of a compound of formula I

in which

R is chosen from halogen, (C₁-C₆)-alkyl which can be substituted by oneor more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy,(C₁-C₆)-alkoxy which can be substituted by one or more fluorine atoms,(C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-((C₁-C₆)-alkyl)amino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro andpentafluorosulfanyl;

R1 is chosen from hydrogen and (C₁-C₆)-alkyl;

R2 is chosen from hydrogen and (C₁-C₆)-alkyl;

R3 is chosen from Br, cyano, (C₁-C₆)-alkoxycarbonyl, —C(═NR4)-NHR5, COOHand —C(═O)—NR6R7;

R4 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyl-oxy,(C₁-C₁₈)-alkylcarbonyl-oxy-(C₁-C₆)-alkoxycarbonyl,(C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryloxycarbonyl, hydroxy,(C₁-C₆)-alkylcarbonyl-oxy, (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkylaminocarbonyl-oxy, di-((C₁-C₆)-alkyl)aminocarbonyl-oxy,(C₁-C₆)-alkylaminocarbonyl and di-((C₁-C₆)-alkyl)aminocarbonyl, whereinall aryl groups can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl;

R5 is chosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy;

or R4 and R5 form together with the —N═C—NH— group which carries them a4-membered to 7-membered, saturated or partially unsaturatedheterocyclic ring which can be substituted by one or more identical ordifferent substituents R1 and which, in addition to the nitrogen atomsbeing part of the —N═C—NH— group, can contain one or two further ringmembers chosen from ═N—, —NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— whichcan be identical or different, with the proviso that two ring membersfrom the series —O—, —S—, —SO—, —SO₂— cannot be present in adjacent ringpositions;

R6 and R7 are independently chosen from hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, —(CH₂)_(o)—(C₆-C₁₄)-aryl and —(CH₂)_(p)-heteroaryl,wherein the aryl and heteroaryl residues can be substituted by one ormore identical or different substituents chosen from halogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl;

or R6 and R7 form together with the nitrogen atom which carries them a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R1 and which, in addition to the nitrogen atomconnecting R6 and R7, can contain one or two further ring members chosenfrom ═N—, —NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— which can beidentical or different, with the proviso that two ring members from theseries —O—, —S—, —SO—, —SO₂— cannot be present in adjacent ringpositions;

n is chosen from 0, 1, 2, 3, 4 and 5;

o and p are independently chosen from 0, 1, 2, 3, 4 and 5;

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, for themanufacture of a medicament for the stimulation of the expression ofendothelial NO synthase and for the treatment of a disease in which sucha stimulation, or an increase in NO level, is desired, for example acardiovascular disorder such as atherosclerosis, coronary artery diseaseor cardiac insufficiency or any other disease mentioned above or belowherein.

An embodiment of the present invention relates to the use of a compoundof formula I, in which

R is chosen from halogen, (C₁-C₆)-alkyl and di-((C₁-C₆)-alkyl)amino;

R1 is hydrogen;

R2 is chosen from hydrogen and (C₁-C₆)-alkyl;

R3 is chosen from Br, cyano, (C₁-C₆)-alkoxycarbonyl, —C(═NR4)-NHR5, COOHand —C(═O)—NR6R7;

R4 is hydrogen;

R5 is hydroxy;

R6 is chosen from hydrogen and (C₁-C₆)-alkyl;

R7 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, phenyland —(CH₂)_(p)-thiazolyl;

or R6 and R7 form together with the nitrogen atom which carries them a4-membered to 7-membered, saturated heterocyclic ring;

n is chosen from 0 and 1;

p is chosen from 0 and 1;

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, for themanufacture of a medicament for the stimulation of the expression ofendothelial NO synthase and for the treatment of a disease in which sucha stimulation, or an increase in NO level, is desired, for example acardiovascular disorder such as atherosclerosis, coronary artery diseaseor cardiac insufficiency or any other disease mentioned above or belowherein.

Another embodiment of the present invention relates to the use of acompound of formula I, in any of its stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio, or a physiologically acceptablesalt thereof, for the manufacture of a medicament for the stimulation ofthe expression of endothelial NO synthase and for the treatment of adisease in which such a stimulation, or an increase in NO level, isdesired, for example a cardiovascular disorder such as atherosclerosis,coronary artery disease or cardiac insufficiency or any other diseasementioned above or below herein, wherein the compound of formula I ischosen from:

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,

6-(3-chloro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,

3-methyl-6-p-tolyl-imidazo[2,1-b]thiazole-2-carboxylic acid ethyl ester,

3-methyl-6-phenyl-imidazo[2,1-b]thiazole-2-carboxylic acid ethyl ester,

6-(4-diethylamino-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid ethyl ester,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidmethyl-phenyl-amide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddimethylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidtert-butylamide,

azetidin-1-yl-[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-methanone,

[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-piperidin-1-yl-methanone,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiethylamide,

[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-pyrrolidin-1-yl-methanone,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidthiazol-2-ylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidcyclopropylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiisopropylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidphenylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(thiazol-2-ylmethyl)-amide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile,

6-(4-fluoro-phenyl)-N-hydroxy-3-methyl-imidazo[2,1-b]thiazole-2-carboxamidine,

2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole, and

6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole-2-carboxylic acid.

Another embodiment of the present invention relates to the use of acompound of formula I, in any of its stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio, or a physiologically acceptablesalt thereof, for the manufacture of a medicament for the stimulation ofthe expression of endothelial NO synthase and for the treatment of adisease in which such a stimulation, or an increase in NO level, isdesired, for example a cardiovascular disorder such as atherosclerosis,coronary artery disease or cardiac insufficiency or any other diseasementioned above or below herein, wherein the compound of formula I is acompound of formula Ia or formula Ib as defined below.

Another subject of the present invention relates to a compound offormula Ia,

in which

R is chosen from halogen, (C₁-C₆)-alkyl which can be substituted by oneor more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy,(C₁-C₆)-alkoxy which can be substituted by one or more fluorine atoms,(C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-((C₁-C₆)-alkyl)amino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro andpentafluorosulfanyl;

R1 is chosen from hydrogen and (C₁-C₆)-alkyl;

R2 is chosen from hydrogen and (C₁-C₆)-alkyl;

R3 is chosen from Br, cyano, —C(═NR4)-NHR5 and —C(═O)—NR6R7;

R4 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyl-oxy,(C₁-C₁₈)-alkylcarbonyl-oxy-(C₁-C₆)-alkoxycarbonyl,(C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryloxycarbonyl, hydroxy,(C₁-C₆)-alkylcarbonyl-oxy, (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkylaminocarbonyl-oxy, di-((C₁-C₆)-alkyl)aminocarbonyl-oxy,(C₁-C₆)-alkylaminocarbonyl and di-((C₁-C₆)-alkyl)aminocarbonyl, whereinall aryl groups can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl;

R5 is chosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy;

or R4 and R5 form together with the —N═C—NH— group which carries them a4-membered to 7-membered, saturated or partially unsaturatedheterocyclic ring which can be substituted by one or more identical ordifferent substituent R1 and which, in addition to the nitrogen atomsbeing part of the —N═C—NH— group, can contain one or two further ringmembers chosen from ═N—, —NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— whichcan be identical or different, with the proviso that two ring membersfrom the series —O—, —S—, —SO—, —SO₂— cannot be present in adjacent ringpositions;

R6 and R7 are independently chosen from hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, —(CH₂)_(o)—(C₆-C₁₄)-aryl and —(CH₂)_(p)-heteroaryl,wherein the aryl and heteroaryl residues can be substituted by one ormore identical or different substituents chosen from halogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl;

or R6 and R7 form together with the nitrogen atom which carries them a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R1 and which, in addition to the nitrogen atomconnecting R6 and R7, can contain one or two further ring members chosenfrom ═N—, —NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— which can beidentical or different, with the proviso that two ring members from theseries —O—, —S—, —SO—, —SO₂— cannot be present in adjacent ringpositions;

n is chosen from 0, 1, 2, 3, 4 and 5;

o and p are independently chosen from 0, 1, 2, 3, 4 and 5;

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, for use as apharmaceutical.

An embodiment of the present invention relates to a compound of formulaIa, in which

R is chosen from halogen;

R1 is hydrogen;

R2 is chosen from (C₁-C₆)-alkyl;

R3 is chosen from Br, cyano, —C(═NR4)-NHR5 and —C(═O)—NR6R7;

R4 is hydrogen;

R5 is hydroxy;

R6 is chosen from hydrogen and (C₁-C₆)-alkyl;

R7 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, phenyland —(CH₂)_(p)-thiazolyl;

or R6 and R7 form together with the nitrogen atom which carries them a4-membered to 7-membered, saturated heterocyclic ring;

n is 1;

p is chosen from 0 and 1;

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, for use as apharmaceutical.

Another embodiment of the present invention relates to a compound offormula I, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, for use as a pharmaceutical, wherein the compound of formula Iis chosen from:

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,

6-(3-chloro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,

3-methyl-6-p-tolyl-imidazo[2,1-b]thiazole-2-carboxylic acid ethyl ester,

6-(4-diethylamino-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid ethyl ester,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidmethyl-phenyl-amide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddimethylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidtert-butylamide,

azetidin-1-yl-[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-methanone,

[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-piperidin-1-yl-methanone,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiethylamide,

[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-pyrrolidin-1-yl-methanone,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidthiazol-2-ylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidcyclopropylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiisopropylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidphenylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(thiazol-2-ylmethyl)-amide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile,

6-(4-fluoro-phenyl)-N-hydroxy-3-methyl-imidazo[2,1-b]thiazole-2-carboxamidine,

2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole, and

6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole-2-carboxylic acid.

Another embodiment of the present invention relates to a compound offormula Ia, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, for use as a pharmaceutical, wherein the compound of formula Iais a compound of formula Ib as defined below.

Another subject of the present invention relates to a compound offormula Ib,

in which

R is chosen from halogen, (C₁-C₆)-alkyl which can be substituted by oneor more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy,(C₁-C₆)-alkoxy which can be substituted by one or more fluorine atoms,(C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-((C₁-C₆)-alkyl)amino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro andpentafluorosulfanyl;

R1 is chosen from hydrogen and (C₁-C₆)-alkyl;

R2 is chosen from hydrogen and (C₁-C₆)-alkyl;

R3 is chosen from Br, cyano and —C(═NR4)-NHR5;

R4 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyl-oxy,(C₁-C₁₈)-alkylcarbonyl-oxy-(C₁-C₆)-alkoxycarbonyl,(C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryloxycarbonyl, hydroxy,(C₁-C₆)-alkylcarbonyl-oxy, (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkylaminocarbonyl-oxy, di-((C₁-C₆)-alkyl)aminocarbonyl-oxy,(C₁-C₆)-alkylaminocarbonyl and di-((C₁-C₆)-alkyl)aminocarbonyl, whereinall aryl groups can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl;

R5 is chosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy;

or R4 and R5 form together with the —N═C—NH— group which carries them a4-membered to 7-membered, saturated or partially unsaturatedheterocyclic ring which can be substituted by one or more identical ordifferent substituents R1 and which, in addition to the nitrogen atomsbeing part of the —N═C—NH— group, can contain one or two further ringmembers chosen from ═N—, —NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— whichcan be identical or different, with the proviso that two ring membersfrom the series —O—, —S—, —SO—, —SO₂— cannot be present in adjacent ringpositions;

n is chosen from 0, 1, 2, 3, 4 and 5;

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof.

An embodiment of the present invention relates to a compound of formulaIb, in which

R is chosen from halogen;

R1 is hydrogen;

R2 is chosen from (C₁-C₆)-alkyl;

R3 is chosen from Br, cyano and —C(═NR4)-NHR5;

R4 is hydrogen;

R5 is hydroxy;

n is 1;

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof.

Another embodiment of the present invention relates to a compound offormula I, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, wherein the compound of formula I is chosen from:

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,

6-(3-chloro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,

3-methyl-6-p-tolyl-imidazo[2,1-b]thiazole-2-carboxylic acid ethyl ester,

6-(4-diethylamino-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid ethyl ester,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidmethyl-phenyl-amide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddimethylamide,

azetidin-1-yl-[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-methanone,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiethylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidthiazol-2-ylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidcyclopropylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiisopropylamide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(thiazol-2-ylmethyl)-amide,

6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile,

6-(4-fluoro-phenyl)-N-hydroxy-3-methyl-imidazo[2,1-b]thiazole-2-carboxamidine,

2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole, and

6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole-2-carboxylic acid.

If in the compounds of formula I, Ia or Ib any groups, substituents,ring members, numbers or other features such as, for example, R, R1,alkyl groups etc. occur several times, they can all independently of oneanother have any of the indicated meanings and can in each case beidentical or different from one another. In a dialkylamino group, forexample, the alkyl groups can be identical or different. The compoundsof formula Ia encompass the compounds of formula Ib. The compounds offormula I encompass the compounds of formula Ib and of formula Ia.

Alkyl residues can be linear, i.e. straight-chain, or branched, acyclicor cyclic. This also applies when they are part of other groups, forexample alkyloxy groups (=alkoxy groups, i.e. alkyl-O— groups),alkyloxycarbonyl groups or alkyl-substituted amino groups, or when theyare substituted. Examples of alkyl groups are methyl, ethyl, propyl,butyl, pentyl, hexyl, the n-isomers of these groups, isopropyl,isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl or3,3-dimethylbutyl. In one embodiment of the invention, a (C₁-C₁₈)-alkylgroup is a (C₁-C₆)-alkyl group. Substituted alkyl groups can besubstituted by one or more, for example one, two, three, four or five,identical or different substituents, for example F, which can be locatedin any desired positions. As far as applicable, the precedingexplanations regarding alkyl groups apply correspondingly to divalentalkyl groups, i.e. alkanediyl groups and alkylene groups, such as amethylene group.

Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl. Substituted cycloalkyl groups can besubstituted by one or more, for example one, two, three, four or five,identical or different substituents which can be located in any desiredpositions.

Examples of (C₆-C₁₄)-aryl residues are phenyl and naphthyl. If a(C₆-C₁₄)-aryl residue, for example phenyl or naphthyl, which can beunsubstituted or substituted, is substituted by one or moresubstituents, in general it can carry one, two, three, four or fiveidentical or different substituents, for example one or twosubstituents. The substituents can be located in any desired positions.This likewise applies to (C₆-C₁₄)-aryl radicals in groups such as, forexample, (C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryloxycarbonyl or(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl. In monosubstituted phenyl groupsthe substituent can be located in the 2-position, the 3-position or the4-position. In disubstituted phenyl groups the substituents can belocated in 2,3-position, 2,4-position, 2,5-position, 2,6-position,3,4-position or 3,5-position. In trisubstituted phenyl groups thesubstituents can be located in 2,3,4-position, 2,3,5-position,2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position.Naphthalenyl (=naphthyl) can be naphthalen-1-yl (=1-naphthyl) ornaphthalen-2-yl (=2-naphthyl). In monosubstituted naphthalen-1-yl groupsthe substituent can be located in the 2-, 3-, 4-, 5-, 6-, 7- or8-position, in monosubstituted naphthalen-2-yl groups the substituentcan be located in the 1-, 3-, 4-, 5-, 6-, 7- or 8-position. Indisubstituted naphthalenyl groups the substituents can likewise occur inany desired positions in the ring via which the naphthalenyl group isbonded, and/or in the other ring.

Heteroaryl groups are preferably 5-membered or 6-membered monocyclicaromatic heterocyclic groups or 9-membered or 10-membered bicyclicaromatic heterocyclic groups, where the bicyclic groups contain a6-membered ring fused to a 5-membered or two fused 6-membered rings. Inbicyclic heteroaryl groups one or both rings can be aromatic and one orboth rings can contain hetero ring members.

Preferably heteroaryl groups contain one, two or three, for example oneor two, identical or different hetero ring members. The ring heteroatomsin heteroaryl groups are generally chosen from N, O and S wherein Nincludes ring nitrogen atoms which carry a hydrogen atom or anysubstituent as is the case in 5-membered aromatic heterocycles such aspyrrole, pyrazole or imidazole, for example. The hetero ring members inheteroaryl groups can be located in any desired positions provided thatthe resulting heterocyclic system is known in the art and is stable andsuitable as a subgroup in a drug substance. Examples of parentheterocycles of heteroaryl groups and other heterocyclic groups arepyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole,1,2,4-triazole, oxazole (=1,3-oxazole), isoxazole (=1,2-oxazole),thiazole (=1,3-thiazole), isothiazole (=1,2-thiazole), tetrazole,pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, indole,benzothiophene, benzofuran, 1,3-benzodioxole(=1,2-methylenedioxybenzene), 1,3-benzoxazole, 1,3-benzothiazole,benzoimidazole, chromane, isochromane, 1,4-benzodioxane(=1,2-ethylenedioxybenzene), quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, phthalazine, thienothiophenes,1,8-naphthyridine. Preferred examples of heteroaryl groups are pyrrole,furan, thiophene, imidazole, oxazole and thiazole, especially thiazole.

The heterocyclic ring which can be formed by R4 and R5 together with the—N═C—NH— group which carries them can be 4-membered, 5-membered,6-membered or 7-membered, and can be partially unsaturated or aromatic,in particular partially unsaturated, and contain, for example, one, twoor three double bonds within the ring, provided the respective ringsystem is known in the art to be stable and suitable as a subgroup in adrug substance. The heterocyclic ring which can be formed by R4 and R5together with the —N═C—NH— group which carries them can contain, inaddition to the nitrogen atoms being part of the —N═C—NH— group, one ortwo further ring members chosen from ═N—, —NR1-, —C(═O)—, —O—, —S—, —SO—and —SO₂—, for example —C(═O)— and —O—, which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —SO—, —SO₂— cannot be present in adjacent ring positions andprovided the respective ring system is known in the art to be stable andsuitable as a subgroup in a drug substance. The heterocyclic ring whichcan be formed by R4 and R5 together with the —N═C—NH— group whichcarries them can be substituted by one or more identical or differentsubstituents R1. Examples of residues of heterocyclic rings formed by R4and R5 together with the —N═C—NH— group which carries them are theresidues of imidazole, dihydro-imidazole, pyrimidine,dihydro-pyrimidine, tetrahydro-pyrimidine, diazepine, dihydro-diazepine,tetrahydro-diazepine, diazet-one, oxadiazole, dihydro-oxadiazole,oxadiazol-one, thiadiazole, dihydro-thiadiazole, thiadiazol-one,triazole, dihydro-triazole, dihydro-triazol-one,dihydro-dioxo-thiadiazole, dihydro-oxo-thiadiazole, dioxo-thiadiazole,dihydro-tetrazole, tetrazole, tetrahydro-triazine, dihydro-triazine,triazine, tetrahydro-tetrazine, dihydro-tetrazine, tetrazine,dihydro-oxadiazine, dioxadiazine, oxadiazine, dihydro-thiadiazine,dithiadiazine, thiadiazine, dihydro-oxadiazin-one, oxadiazin-one,pyrimidine-dione, tetrahydro-oxadiazepine, dihydro-oxadiazepine,oxadiazepine, tetrahydro-thiadiazepine, dihydro-thiadiazepine,thiadiazepine, tetrahydro-triazepine, dihydro-triazepine or triazepine.

The heterocyclic ring which can be formed by R6 and R7 together with thenitrogen atom which carries them can be 4-membered, 5-membered,6-membered or 7-membered, and can be saturated, partially unsaturated oraromatic, in particular saturated, and contain, for example, one, two orthree double bonds within the ring, provided the respective ring systemis known in the art to be stable and suitable as a subgroup in a drugsubstance. The heterocyclic ring which can be formed by R6 and R7together with the nitrogen atom which carries them can contain, inaddition to the nitrogen atom connecting R6 and R7, one or two furtherring members chosen from ═N—, —NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂—,for example —C(═O)— and —O—, which can be identical or different, withthe proviso that two ring members from the series —O—, —S—, —SO—, —SO₂—cannot be present in adjacent ring positions and provided the respectivering system is known in the art to be stable and suitable as a subgroupin a drug substance. The heterocyclic ring which can be formed by R6 andR7 together with the nitrogen atom which carries them can be substitutedby one or more identical or different substituents R1. Examples ofresidues of heterocyclic rings formed by R6 and R7 together with thenitrogen atom which carries them are the residues of azetidine,pyrrolidine, piperidine, azepane, dihydro-azete, azete, dihydro-pyrrole,pyrrole, tetrahydro-pyridine, dihydro-pyridine, pyridine,tetrahydro-azepine, dihydro-azepine, azepine, imidazoline,hexahydro-pyrimidine, piperazine, diazepane, dihydro-imidazole,tetrahydro-pyrimidine, tetrahydro-diazepine, imidazole,dihydro-pyrimidine, pyrimidine, tetrahydro-pyrazine, dihydro-pyrazine,pyrazine, dihydro-diazepine, diazepine, oxazolidine, morpholine,oxazinane, oxazepane, oxazole, thiazole, thiazolidine, thiazinane,thiomorpholine, oxazepine, thiazepine, thiazepane,1,1-dioxo-thiazolidine, 1,1-dioxo-thiazinane, 1,1-dioxo-thiomorpholine,1,1-dioxo-thiazepane, pyrrolidinone, piperidinone or azepanone,preferably pyrrolidine, piperidine or azepane.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine,chlorine or bromine, more preferably fluorine or chlorine, for examplefluorine.

An oxo group, when bonded to a carbon atom, replaces two hydrogen atomson a carbon atom of the parent system. Thus, if a CH₂ group issubstituted by oxo, i.e. by a doubly bonded oxygen atom, it becomes aC(═O) group. Evidently, an oxo group cannot occur as a substituent on acarbon atom in an aromatic ring.

The present invention includes all stereoisomeric forms of the compoundsof formula I, Ia or Ib and their salts. With respect to each chiralcenter, independently of any other chiral center, the compounds offormula I, Ia or Ib can be present in S configuration or substantially Sconfiguration, or in R configuration or substantially R configuration,or as a mixture of the S isomer and the R isomer in any ratio. Theinvention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, compoundsaccording to the invention which can exist as enantiomers can be presentin enantiomerically pure form, both as levorotatory and asdextrorotatory antipodes, and in the form of mixtures of the twoenantiomers in all ratios including racemates. In the case of a E/Zisomerism, or cis/trans isomerism, for example on double bonds or rings,the invention includes both the E form and Z form, or the cis form andthe trans form, as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, for example,by separation of a mixture of isomers by customary methods, for exampleby chromatography or crystallization, by the use of stereochemicallyuniform starting materials in the synthesis, or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at the stage of the compound of formulaI, Ia or Ib or at the stage of a starting material or an intermediateduring the synthesis.

The present invention also includes all tautomeric forms of thecompounds of formulae I, Ia and Ib and their salts. For example, theinvention includes the tautomeric forms of the group —C(═NR4)-NHR5:

In case a compound of formula I, Ia or Ib contains one or more acidicand/or basic groups, i.e. salt-forming groups, the invention alsocomprises its corresponding physiologically or toxicologicallyacceptable salts, i.e. non-toxic salts, in particular itspharmaceutically acceptable salts. Thus, the compounds of formulae I, Iaand Ib which contain an acidic group can be present, and can be usedaccording to the invention, for example, as alkali metal salts, alkalineearth metal salts or as ammonium salts. More specific examples of suchsalts include sodium salts, potassium salts, calcium salts, magnesiumsalts, quaternary ammonium salts such as tetraalkylammonium salts, oracid addition salts with ammonia or organic amines such as, for example,ethylamine, ethanolamine, triethanolamine or amino acids. Compounds offormulae I, Ia and Ib which contain a basic group, i.e. a group whichcan be protonated, can be present, and can be used according to theinvention, for example, in the form of their addition salts withinorganic or organic acids. Examples for suitable acids include hydrogenchloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid,methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonicacids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylicacid, benzoic acid, formic acid, propionic acid, pivalic acid,diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid,gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, citricacid, adipic acid, and other acids known to the person skilled in theart. If compound of formula I, Ia or Ib simultaneously contains acidicand basic groups in the molecule, the invention also includes, inaddition to the salt forms mentioned, inner salts or betaines orzwitterions. The salts of the compounds of formulae I, Ia and Ib can beobtained by customary methods which are known to the person skilled inthe art like, for example, by contacting the compound of formula I, Iaor Ib with an organic or inorganic acid or base in a solvent or diluent,or by anion exchange or cation exchange from another salt. The presentinvention also includes all salts of the compounds of formulae I, Ia andIb which, owing to low physiological compatibility, are not directlysuitable for use in pharmaceuticals but which can be used, for example,as intermediates for chemical reactions or for the preparation ofphysiologically acceptable salts.

The present invention furthermore includes all solvates of compounds offormulae I, Ia and Ib, for example hydrates or adducts with alcohols,active metabolites of the compounds of formulae I, Ia and Ib, and alsoprodrugs and derivatives of the compounds of formulae I, Ia and Ib whichin vitro may not necessarily exhibit pharmacological activity but whichin vivo are converted into pharmacologically active compounds, forexample esters or amides of carboxylic acid groups.

In one embodiment of the invention, R in the compounds of formulae I, Iaand Ib is chosen from halogen, (C₁-C₆)-alkyl which can be substituted byone or more fluorine atoms, (C₁-C₆)-alkoxy which can be substituted byone or more fluorine atoms, and di-((C₁-C₆)-alkyl)amino, which lattergroup can also be represented as di-(C₂-C₁₂)-alkylamino. In thecompounds of formula I R is preferably chosen from halogen, for exampleF and Cl, (C₁-C₆)-alkyl, for example methyl, anddi-((C₁-C₆)-alkyl)amino, for example diethylamino. In the compounds offormulae Ia and Ib R is preferably chosen from halogen and can be F, forexample. If the number n in a compound of formula I, Ia or Ib is 0(zero), the phenyl group carrying the groups R carries five hydrogenatoms and thus is an unsubstituted phenyl group. If the number n isdifferent from 0 and the phenyl group thus is substituted by one or moregroups R, all positions of the phenyl group which do not carry a groupR, carry hydrogen atoms. For example, if n is 1, the phenyl groupcarries four hydrogen atoms in addition to one group R. Instead ofincluding in the definition of the number n the denotation 0 in additionto denotations which are different from 0, and including in thedefinition of the group R only denotations which are different fromhydrogen, the compounds of formulae I, Ia and Ib can likewise be definedby including in the definition of the number n only denotations whichare different from 0, and including in the definition of the group R thedenotation hydrogen in addition to the denotations which are differentfrom hydrogen.

In one embodiment R1 in the compounds of formulae I, Ia and Ib is chosenfrom hydrogen and methyl, and preferably is hydrogen.

In one embodiment R2 in the compounds of formulae I, Ia and Ib is chosenfrom hydrogen, methyl and ethyl, and preferably is chosen from hydrogenand methyl.

In one embodiment a (C₁-C₆)-alkoxycarbonyl group representing R3 in thecompounds of formula I is chosen from methoxycarbonyl andethoxycarbonyl. In the compounds of formula I R3 is preferably chosenfrom Br, cyano, —C(═NR4)-NHR5 and —C(═O)—NR6R7, more preferably from Br,cyano and —C(═NR4)-NHR5. In one embodiment of the invention, in thecompounds of formula Ia R3 is chosen from Br, cyano and —C(═NR4)-NHR5.In another embodiment of the invention, in the compounds of formula IaR3 is chosen from —C(═O)—NR6R7. In one embodiment of the invention, inthe compounds of formula Ib R3 is chosen from Br and cyano. In anotherembodiment of the invention, in the compounds of formula Ib R3 is chosenfrom —C(═NR4)-NHR5.

In one embodiment of the invention in the compounds of formulae I, Iaand Ib R2 is defined as hydrogen when R3 is defined as Br.

In another embodiment in the compounds of formula I R2 is defined ashydrogen or methyl when R3 is defined as COOH.

In another embodiment in the compounds of formula I R2 is defined asmethyl when R3 is defined as cyano, (C₁-C₆)-alkoxycarbonyl,—C(═NR4)-NHR5 or —C(═O)—NR6R7.

In another embodiment in the compounds of formula Ia R2 is defined asmethyl when R3 is defined as cyano, —C(═NR4)-NHR5 or —C(═O)—NR6R7.

In another embodiment in the compounds of formula Ib R2 is defined asmethyl when R3 is defined as cyano or —C(═NR4)-NHR5.

In one embodiment of the invention in the compounds of formulae I, Iaand Ib R4 is defined as hydrogen or (C₁-C₆)-alkyl and preferably ishydrogen.

In one embodiment of the invention in the compounds of formulae I, Iaand Ib R5 is defined as hydrogen or hydroxy and preferably is hydroxy.

In one embodiment of the invention R4 and R5 in the compounds offormulae I, Ia and Ib form together with the —N═C—NH— group whichcarries them a 4-membered to 7-membered, for example a 5- or 6-membered,saturated or partially unsaturated heterocyclic ring which can besubstituted by one or more identical or different substituents R1 andwhich, in addition to the nitrogen atoms being part of the —N═C—NH—group, can contain one or two further ring members chosen from ═N—,—NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —SO—, —SO₂— cannot be present in adjacent ring positions, and, forexample, R4 and R5 in the compounds of formulae I, Ia and Ib formtogether with the —N═C—NH— group which carries them a residue of a ringchosen from imidazole, dihydro-imidazole, pyrimidine,dihydro-pyrimidine, tetrahydro-pyrimidine, diazepine, dihydro-diazepine,tetrahydro-diazepine, diazet-one, oxadiazole, dihydro-oxadiazole,oxadiazol-one, thiadiazole, dihydro-thiadiazole, thiadiazol-one,triazole, dihydro-triazole, dihydro-triazol-one,dihydro-dioxo-thiadiazole, dihydro-oxo-thiadiazole, dioxo-thiadiazole,dihydro-tetrazole, tetrazole, tetrahydro-triazine, dihydro-triazine,triazine, tetrahydro-tetrazine, dihydro-tetrazine, tetrazine,dihydro-oxadiazine, dioxadiazine, oxadiazine, dihydro-thiadiazine,dithiadiazine, thiadiazine, dihydo-oxadiazin-one, oxadiazin-one,pyrimidine-dione, tetrahydro-oxadiazepine, dihydro-oxadiazepine,oxadiazepine, tetrahydro-thiadiazepine, dihydro-thiadiazepine,thiadiazepine, tetrahydro-triazepine, dihydro-triazepine and triazepine.

In one embodiment R6 in the compounds of formulae I and Ia is chosenfrom hydrogen and (C₁-C₆)-alkyl and preferably is chosen from hydrogen,methyl, ethyl and isopropyl.

In one embodiment R7 in the compounds of formulae I and Ia is chosenfrom hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, —(CH₂)_(o)-aryl and—(CH₂)_(p)-heteroaryl, wherein the aryl and heteroaryl residues can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl.Preferably in the compounds of formulae I and Ia R7 is defined ashydrogen, (C₁-C₆)-alkyl, for example methyl, ethyl, isopropyl ortert-butyl, (C₃-C₇)-cycloalkyl, for example cyclopropyl, phenyl or—(CH₂)_(p)-thiazolyl, for example thiazolyl or thiazolylmethyl.

In one embodiment of the invention R6 and R7 in the compounds offormulae I and Ia form together with the nitrogen atom which carriesthem a 4-membered to 7-membered, saturated, partially unsaturated oraromatic heterocyclic ring, which can be substituted by one or moreidentical or different substituents R1 and which, in addition to thenitrogen atom connecting R6 and R7, can contain one or two further ringmembers chosen from ═N—, —NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— whichcan be identical or different, with the proviso that two ring membersfrom the series —O—, —S—, —SO—, —SO₂— cannot be present in adjacent ringpositions, and, for example, R6 and R7 in the compounds of formulae Iand Ia form together with the nitrogen atom which carries them a residueof a ring chosen from azetidine, pyrrolidine, piperidine, azepane,dihydro-azete, azete, dihydro-pyrrole, pyrrole, tetrahydro-pyridine,dihydro-pyridine, pyridine, tetrahydro-azepine, dihydro-azepine,azepine, imidazoline, hexahydro-pyrimidine, piperazine, diazepane,dihydro-imidazole, tetrahydro-pyrimidine, tetrahydro-diazepine,imidazole, dihydro-pyrimidine, pyrimidine, tetrahydro-pyrazine,dihydro-pyrazine, pyrazine, dihydro-diazepine, diazepine, oxazolidine,morpholine, oxazinane, oxazepane, oxazole, thiazole, thiazolidine,thiazinane, thiomorpholine, oxazepine, thiazepine, thiazepane,1,1-dioxo-thiazolidine, 1,1-dioxo-thiazinane, 1,1-dioxo-thiomorpholine,1,1-dioxo-thiazepane, pyrrolidinone, piperidinone and azepanone,preferably from pyrrolidine, piperidine and azepane. In one embodimentof the invention, R6 and R7 in the compounds of formulae I and Ia formtogether with the nitrogen atom which carries them a 4-membered to7-membered, saturated, partially unsaturated or aromatic heterocyclicring, in particular a saturated or partially unsaturated ring, andpreferably R6 and R7 form together with the nitrogen atom which carriesthem a 4-membered to 7-membered, saturated heterocyclic ring, forexample a residue of pyrrolidine, piperidine or azepane.

In one embodiment in the compounds of formulae I, Ia and Ib the number nis chosen from 0, 1 and 2, preferably from 0 and 1. In anotherembodiment n is 1.

In one embodiment in the compounds of formulae I and Ia the number o ischosen from 0 and 1 and preferably is 0.

In one embodiment in the compounds of formulae I and Ia the number p ischosen from 0, 1 and 2 and preferably from 0 and 1.

The compounds according to formulae I, Ia and Ib and their precursorscan be prepared according to methods published in the literature or,respectively, to analogous methods. For example, the compounds offormula I, including the compounds of formulae Ia and Ib, can beprepared by reacting a compound of formula II with a compound of formulaIII.

In the compounds of formulae II and III the variables R, R1, R2, R3 andn are defined as in the compounds of formula I and X is a leaving groupsuch as halogen, in particular Br. The reaction of the compounds offormulae II and III can be carried out in an inert solvent which can beprotic or aprotic and aqueous or non-aqueous, for example hexane,toluene, dichloromethane, dichloroethane, trichloromethane,tetrachloromethane, an ether, for example diethyl ether, tetrahydrofuran(=THF) or dioxane, an amide, for example N,N-dimethylformamide (=DMF),an alcohol, for example methanol or ethanol, water or acetonitrile, or amixture of two or more solvents, including a mixture of water and anorganic solvent which is miscible or immiscible with water.Alternatively, the reaction can be carried out under solvent-freeconditions. The reaction can also be carried out in the presence of aLewis acid or with microwave irradiation. The reaction of the compoundsof formulae II and III can be carried out in a wide temperature range.Usually it is advantageous to perform the reaction at temperatures fromabout −20° C. to about the boiling point of the solvent used, preferablyat from about 0° C. to about 140° C., more preferably at about theboiling point of the solvent. As is usual, the detailed conditions of aspecific preparation, including the solvent, the addition of a base, thetemperature, the order of addition, the molar ratios and otherparameters, are routinely chosen by the person skilled in the art inview of the characteristics of the starting compounds and the targetcompound. Appropriate methods have been published, for example, in Pylet al., Liebigs Ann. Chem. 643 (1961), 145-153; Pyl et al., Liebigs Ann.Chem. 657 (1962), 108-113; Pyl et al., Liebigs Ann. Chem. 657 (1962),113-120; Sayed et al., Synth. Commun. 32 (2002), 481-495.

All reactions used in the above-described syntheses of the compounds offormula I are per se well-known to the skilled person and can be carriedout under standard conditions according to or analogously to proceduresdescribed in the literature, for example in Houben-Weyl, Methoden derOrganischen Chemie (Methods of Organic Chemistry), Thieme-Verlag,Stuttgart; or Organic Reactions, John Wiley & Sons, New York. Dependingon the circumstances of the individual case, in order to avoid anunwanted course of a reaction or side reactions during the synthesis ofa compound, it can generally be necessary or advantageous to temporarilyblock functional groups by introducing protective groups and deprotectthem at a later stage of the synthesis, or introduce functional groupsin the form of precursor groups which later are converted into thedesired functional groups. As examples of protecting groupsamino-protecting groups, such as tert-butyloxycarbonyl andbenzyloxycarbonyl, and protecting groups of carboxylic acid groups,which can be protected as esters such as tert-butyl esters, which can bedeprotected by treatment with trifluoroacetic acid, or benzyl esters,which can be deprotected by catalytic hydrogenation, may be mentioned.As an example of a precursor group, the nitro group may be mentionedwhich can be converted into an amino group by reduction, for example bycatalytic hydrogenation. Such synthesis strategies, and protectivegroups and precursor groups which are suitable in a specific case, areknown to the skilled person. Another type of conversion is starting fromcompounds of formula I wherein R3 is a carboxylic acid ester group. Bystandard procedures described in the literature, the ester group can betransferred to an amide groups by direct reaction with ammonia or anamine or indirectly via saponification of the ester group and reactionof the free carboxylic acid with ammonia or an amine. The primary amideobtained with ammonia can be dehydrated to get the correspondingnitrile. Numerous procedures are described in the literature to conductsuch types of reactions, for example in D. S. Bose et al., Synthesis(1999), 64-65. Nitriles are easily converted by addition ofnitrogen-containing compounds such as amines or hydroxylamines toadducts like amidines or hydroxy-amidines. Numerous such procedures aredescribed in the literature, for example in Houben-Weyl, Methoden derOrganischen Chemie (Methods of Organic Chemistry) volume XI/2, pp. 39-,Thieme-Verlag, Stuttgart; G. Wagner et al., Pharmazie 29 (1974), 12-15;Z. Li et al, J. Med. Chem. 48 (2005), 6169-6173; M. D. Bjorklund et al.,J. Heterocycl. Chem. 17 (1980), 819-821.

If desired, the obtained compounds of formula I, as well as anyintermediate compounds, can be purified by customary purificationprocedures, for example by recrystallization or chromatography. Thestarting compounds of formulae II and III for the preparation of thecompounds of formula I are commercially available or can be preparedaccording to or analogously to literature procedures.

The compounds of formulae I, Ia and Ib are useful pharmacologicallyactive, or pharmaceutically active, compounds which modulate theexpression of endothelial NO synthase, and more specifically upregulate,or stimulate, the expression, or transcription, of endothelial NOsynthase, and which can be employed as pharmaceuticals, or activeingredients of medicaments, for the treatment of various diseases. Inthe context of the present invention, treatment is understood ascomprising both therapy, including alleviation and cure, of diseases anddisease symptoms and prevention and prophylaxis of diseases and diseasesymptoms, such as, for example, the prevention of the appearance ofasthmatic disease symptoms or the prevention of myocardial infarction orof myocardial reinfarction in affected patients. The diseases or diseasesymptoms can be acute or chronic. Diseases which can be treated with thecompounds of formulae I, Ia and Ib include, for example, cardiovasculardiseases like stable and unstable angina pectoris, coronary heartdisease, coronary artery disease, Prinzmetal angina (spasm), acutecoronary syndrome, cardiac insufficiency, heart failure, myocardialinfarction, stroke, thrombosis, peripheral artery occlusive disease(=PAOD), endothelial dysfunction, atherosclerosis, restenosis,endothelial damage after PTCA (=percutaneous transluminal coronaryangioplasty), hypertension including essential hypertension, pulmonaryhypertension and secondary hypertension (renovascular hypertension,chronic glomerulonephritis), erectile dysfunction, and ventriculararrhythmia. Further, the compounds of formulae I, Ia and Ib lower thecardiovascular risk of postmenopausal women or after intake ofcontraceptives. Compounds of formulae I, Ia and Ib can additionally beused in the treatment, including therapy and prevention, of diabetes anddiabetes complications such as nephropathy or retinopathy, angiogenesis,bronchial asthma, chronic renal failure, cirrhosis of the liver,osteoporosis, restricted memory performance or a restricted ability tolearn. Preferred indications are chronic heart failure, stable anginapectoris, coronary heart disease, hypertension, endothelial dysfunction,atherosclerosis and diabetes complications.

The compounds of formulae I, Ia and Ib can be used in combination withother pharmacologically active compounds or pharmaceuticals, preferablywith compounds which are able to enhance the effect of the compoundsaccording to formulae I, Ia and Ib. Examples of such other compoundsinclude statins; ACE inhibitors; AT1 antagonists; argininase inhibitors;PDE V inhibitors; calcium antagonists; alpha blockers; beta blockers;metimazol and analogous compounds; arginine; tetrahydrobiopterin;vitamins, in particular vitamin C and vitamin B6; niacine.

The compounds of formulae I, Ia and Ib and their physiologicallyacceptable salts, optionally in combination with other pharmacologicallyactive compounds, can be administered to animals, preferably to mammals,and in particular to humans, as pharmaceuticals by themselves, inmixtures with one another, or in the form of pharmaceuticalcompositions. Further subjects of the present invention therefore alsoare the compounds of formulae Ia and Ib and their physiologicallyacceptable salts for use as pharmaceuticals, the use of the compounds offormulae I, Ia and Ib and their physiologically acceptable salts asmodulating agents, and more specifically as stimulating agents orupregulating agents, of the expression or transcription of endothelialNO synthase, for example in conditions in which an increased expressionof said enzyme or an increased NO level or the normalization of adecreased NO level in a patient is desired, and in particular their usein the treatment, including therapy and prevention, of theabove-mentioned diseases or syndromes, as well as their use for thepreparation or manufacture of medicaments for these purposes.Furthermore, a subject of the present invention are pharmaceuticalcompositions, or pharmaceutical preparations, which comprise aneffective dose of at least one compound of formula Ia or Ib and/or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier, i.e. one or more pharmaceutically acceptable carriersubstances and/or additives.

The pharmaceuticals according to the invention can be administeredorally, for example in the form of pills, tablets, lacquered tablets,sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous,alcoholic or oily solutions, syrups, emulsions or suspensions, orrectally, for example in the form of suppositories.

Administration can also be carried out parenterally, for examplesubcutaneously, intramuscularly or intravenously, for example in theform of solutions for injection or infusion. Other suitableadministration forms are, for example, percutaneous or topicaladministration, for example in the form of ointments, tinctures, spraysor transdermal therapeutic systems, or the inhalative administration inthe form of nasal sprays or aerosol mixtures, or, for example,microcapsules, implants or rods. The preferred administration formdepends, among others, on the disease to be treated and on its severity.

The amount of a compound of formula I, Ia or Ib and/or itsphysiologically acceptable salts present in the pharmaceuticalcompositions normally ranges from about 0.2 to about 800 mg, preferablyfrom about 0.5 to about 500 mg, in particular from about 1 to about 200mg, per dose, but depending on the type of the pharmaceuticalcomposition it may also be higher. The pharmaceutical compositionsusually comprise from about 0.5 to about 90 percent by weight of thecompounds of formula I or Ia or Ib and/or their physiologicallyacceptable salts. The production of the pharmaceutical compositions canbe carried out in a manner known per se. To this end, one or morecompounds of formula I or Ia or Ib and/or their physiologicallyacceptable salts together with one or more solid or liquidpharmaceutical carrier substances (or vehicles) and/or additives (orauxiliary substances) and, if a combination medicament is desired, otherpharmacologically active compounds having therapeutic or prophylacticaction are brought into a suitable administration form or dosage formwhich can then be used as a pharmaceutical in human or veterinarymedicine.

For the production of pills, tablets, sugar-coated tablets and hardgelatin capsules it is possible to use, for example, lactose, starch,for example maize starch, starch derivatives, talc, stearic acid or itssalts, etc. Soft gelatin capsules and suppositories can comprise, forexample, fats, waxes, semisolid and liquid polyols, natural or hardenedoils, etc. Suitable carrier substances for the preparation of solutions,for example of solutions for injection, or of emulsions or syrups are,for example, water, physiologically sodium chloride solution, alcoholssuch as ethanol, glycerol, polyols, sucrose, invert sugar, glucose,mannitol, vegetable oils, etc. It is also possible to lyophilize thecompounds of formulae I, Ia and Ib and their physiologically acceptablesalts and to use the resulting lyophilizates, for example, for preparingcompositions for injection or infusion. Suitable carriers formicrocapsules, implants or rods are, for example, copolymers of glycolicacid and lactic acid. Besides the compound or compounds according to theinvention and carrier substances, the pharmaceutical compositions canalso contain additives such as, for example, fillers, disintegrants,binders, lubricants, wetting agents, stabilizers, emulsifiers,dispersants, preservatives, sweeteners, colorants, flavorings,aromatizers, thickeners, diluents, buffer substances, solvents,solubilizers, agents for achieving a depot effect, salts for alteringthe osmotic pressure, coating agents or antioxidants.

The dosage of the compound of formula I, Ia or Ib to be administeredand/or of a physiologically acceptable salt thereof depends on theindividual case and, as is customary, has to be adapted to theindividual circumstances to achieve an optimum effect. Thus, it dependson the nature and the severity of the disorder to be treated, and alsoon the sex, age, weight and individual responsiveness of the human oranimal to be treated, on the efficacy and duration of action of thecompounds used, on whether the use is for the therapy of a acute orchronic disease or prophylactic, or on whether other active compoundsare administered in addition to compounds of formula I or Ia Ib. Ingeneral, a daily dose from about 0.01 mg/kg to about 100 mg/kg,preferably from about 0.1 mg/kg to about 10 mg/kg, in particular fromabout 0.3 mg/kg to about 5 mg/kg (in each case mg per kg of bodyweight)is appropriate for administration to an adult weighing about 75 kg inorder to obtain the desired results. The daily dose can be administeredin a single dose or, in particular when larger amounts are administered,divided into several, for example two, three or four individual doses.In some cases, depending on the individual response, it may be necessaryto deviate upwards or downwards from the given daily dose.

The compounds of formulae I, Ia and Ib can also be used for otherpurposes than those indicated in the foregoing. Non-limiting examplesinclude the use as diagnostics, for example the use in methods fordetermining the activity of endothelial NO synthase in biologicalsamples, the use as biochemical tools and the use as intermediates forthe preparation of further compounds, for example furtherpharmacologically active compounds.

List of Abbreviations:

-   -   DMF N,N-dimethylformamide    -   HPLC high performance liquid chromatography    -   RP reversed phase    -   RT room temperature    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TOTU        O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium        tetrafluoroborate

EXAMPLES Example 16-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester

2-Bromo-1-(4-fluoro-phenyl)-ethanone (200 mg, 0.92 mmol) and2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (186.2 mg, 0.92mmol) were heated in 5 ml of ethanol at 95° C. for 5 hours. Afteraddition of 80 mg of 2-bromo-1-(4-fluoro-phenyl)-ethanone and furtherheating for 9 hours at 95° C. the mixture was evaporated. Addition ofpotassium hydrogensulfate solution, extraction with ethyl acetate andpurification by preparative HPLC (RP18, acetonitrile/water 0.1% TFA)yielded 81 mg (32%) of the desired product. MS (mass spectrum):M+H⁺=305.07.

Example 26-(3-Chloro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester

The compound was synthesized analogously to example 1 using2-bromo-1-(3-chloro-phenyl)-ethanone. Yield: 30%. MS: M+H⁺=321.01.

Example 3 3-Methyl-6-p-tolyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester

The compound was synthesized analogously to example 1 using2-bromo-1-p-tolyl-ethanone. Yield: 26%. MS: M+H⁺=301.02.

Example 4 3-Methyl-6-phenyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester

The compound was synthesized analogously to example 1 using2-bromo-1-phenyl-ethanone. Yield: 36%. MS: M+H⁺=287.23.

Example 56-(4-Diethylamino-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid ethyl ester

The compound was synthesized analogously to example 1 using2-bromo-1-(4-diethylamino-phenyl)-ethanone. Yield: 85%. MS: M+H⁺=358.18.

Example 66-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidmethyl-phenyl-amide

6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(example 7, 50 mg, 0.18 mmol) N-methyl-phenyl-amine (29.15 mg, 0.27mmol), TOTU (63.32 mg, 0.2 mmol) and triethylamine (100.6 μl, 0.72 mmol)in 3 ml DMF were stirred at RT for 8 hours. The mixture was evaporated.Ethyl acetate and water were added, the organic layer was separated,washed with water, dried and evaporated. The crude product was purifiedby preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 9 mg(14%) of the desired product. MS: M+H⁺=365.94.

Example 76-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid

To lithium hydroxide (184.4 mg, 7.7 mmol) in 100 ml of ethanol and 100ml of water was added6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester (example 1, 2.13 g, 7 mmol). After stirring 24 hours at RTthe mixture was filtered and the filtrate partially evaporated. Theaqueous solution was acidified with hydrochloric acid to pH 4 and theseparated product filtered and dried. Yield: 1.11 g (57%). MS:M+H⁺=277.01.

Example 86-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidamide

6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(example 7, 50 mg, 0.18 mmol), ammonium chloride (19.4 mg, 0.36 mmol),TOTU (63.32 mg, 0.2 mmol) and triethylamine (100.6 μl, 0.72 mmol) in 3ml DMF were stirred at RT for 8 hours. The mixture was evaporated. Ethylacetate and water were added, the organic layer was separated, washedwith water, dried and evaporated. The crude product was purified bypreparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 14 mg(28%) of the desired product. MS: M+H⁺=276.03.

Example 96-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddimethylamide

The compound was synthesized analogously to example 8 usingdimethylamine hydrochloride. Yield: 46%. MS: M+H⁺=304.05.

Example 106-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidtert-butylamide

The compound was synthesized analogously to example 8 usingtert-butylamine. Yield: 48%. MS: M+H⁺=332.05.

Example 11Azetidin-1-yl-[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-methanone

The compound was synthesized analogously to example 8 using azetidine.Yield: 22%. MS: M+H⁺=315.96.

Example 12[6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-piperidin-1-yl-methanone

The compound was synthesized analogously to example 8 using piperidine.Yield: 27%. MS: M+H⁺=343.97.

Example 136-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiethylamide

The compound was synthesized analogously to example 8 using diethylaminehydrochloride. Yield: 39%. MS: M+H⁺=332.07.

Example 14[6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-pyrrolidin-1-yl-methanone

The compound was synthesized analogously to example 8 using pyrrolidine.Yield: 22%. MS: M+H⁺=329.96.

Example 156-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidthiazol-2-ylamide

The compound was synthesized analogously to example 8 usingthiazol-2-ylamine. Yield: 12%. MS: M+H⁺=358.90.

Example 166-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidcyclopropylamide

The compound was synthesized analogously to example 8 usingcyclopropylamine. Yield: 16%. MS: M+H⁺=315.98.

Example 176-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiisopropylamide

The compound was synthesized analogously to example 8 usingdiisopropylamine. Yield: 11%. MS: M+H⁺=360.09.

Example 186-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidphenylamide

The compound was synthesized analogously to example 8 using phenylamine.Yield: 11%. MS: M+H⁺=351.96.

Example 196-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(thiazol-2-ylmethyl)-amide

The compound was synthesized analogously to example 8 using(thiazol-2-ylmethyl)-amine. Yield: 18%. MS: M+H⁺=372.91.

Example 206-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile

6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidamide (example 8, 190 mg, 0.69 mmol) was dissolved in 10 ml ofdichloromethane. The solution was cooled to 0° C., triethylamine (191.8μl, 1.38 mmol) was added and trifluoromethanesulfonic acid anhydride(214 mg, 0.76 mmol) was added dropwise. The mixture was allowed to warmto RT. Three more equivalents of trifluoromethanesulfonic acid anhydridewere added and the mixture was stirred for one hour after each addition.The reaction was quenched by addition of water and extracted withdichloromethane. The organic layer was washed with brine and dilutedhydrochloric acid, dried and evaporated. Yield: 85%. MS: M+H⁺=258.04.

Example 216-(4-Fluoro-phenyl)-N-hydroxy-3-methyl-imidazo[2,1-b]thiazole-2-carboxamidine

6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile(example 20, 140 mg, 0.54 mmol), hydroxylamine hydrochloride (226.9 mg,3.26 mmol) and triethylamine (529 μl, 3.8 mmol) were stirred in 10 ml ofisopropanol at 90° C. for 2 hours. The solvent was removed in vacuo andwater was added. The solid was filtered, washed with dilutedhydrochloric acid and water and was dried. Yield: 63%. MS: M+H⁺=291.15.

Example 22 2-Bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole

To a solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (2 g, 9.215 mmol)in 100 ml ethanol were added 5-bromo-thiazol-2-ylamine hydrobromide(2.396 g, 9.215 mmol) and ethyl-diisopropyl-amine (1.19 g, 9.215 mmol).The mixture was stirred under reflux for 8 h and evaporated. Water wasadded to the residue and extracted with ethyl acetate. The organic layerwas separated, washed with water, dried and evaporated. The crudeproduct was purified by preparative HPLC (RP18, acetonitrile/water 0.1%TFA) to yield 532 mg (20%) of the desired product. MS: M+H⁺=296.96.

Example 23 6-(4-Fluoro-phenyl)-imidazo[2,1-b]thiazole-2-carboxylic acid

To a solution of 2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole(example 22, 100 mg, 0.336 mmol) in 5 ml THF were added 200 μlbutyllithium (2.5 M) in hexane at −60° C. The mixture was stirred for 10min, solid carbon dioxide was added and the mixture was allowed to warmat RT. The solution was quenched with methanol and water, acidified andextracted with ethyl acetate. The organic layer was separated, washedwith water, dried and evaporated. The crude product was purified bypreparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 9 mg (10%)of the desired product. MS: M+H⁺=263.03.

Determination of the Biological Activity

A) Activation of eNOS Transcription

Activation of eNOS transcription was measured as described in detail byLi et al., “Activation of protein kinase C alpha and/or epsilon enhancestranscription of the human endothelial nitric oxide synthase gene”, Mol.Pharmacol. 53 (1998), 630-637. Briefly, a 3.5 kB long fragment 5′ of thestarting codon of the eNOS gene was cloned, sequenced and cloned infirefly luciferase expression plasmids to monitor activation of the eNOSpromoter by reporter gene activity. A human endothelial cell line stabletransfected and expressing this promoter-reporter construct was used forcompound testing. Cells were incubated for 18 h with the compounds.

All compounds were dissolved in sterile dimethyl sulfoxide (DMSO). Afinal concentration of 0.5% DMSO in complete medium was allowed.Induction of reporter gene expression in these cells was measured usinga standard luciferase assay system (Promega, Cat. No. E150) according tothe manufacturer's instructions. Luciferase induction in cells incubatedwith compounds were compared to those incubated with solvent alone. Theratio of both activities (transcription induction ratio, TIR) wasplotted as a function of compound concentration. Typically, TIR valuesstarted at low concentrations at a ratio of 1, indicating no compoundeffect, and extended up to a maximum TIR value TIR(max) which indicatesthe increase of the eNOS transcription. EC₅₀ values of transcriptioninduction ratios as a function of compound concentration were determinedgraphically.

Numerous compounds of the instant invention were tested by theabove-described assay and found to increase protein transcription.Generally, the tested compounds exhibited EC₅₀ values of less than about50 μM. Preferred compounds exhibited EC₅₀ values of from about 5 μM toabout 0.5 μM. More preferred compounds, for example the compounds ofexamples 1, 2, 3, 10 and 22, exhibited EC₅₀ values of less than 0.5 μM.

The effect of compounds on eNOS-transcription was confirmed in a secondassay based on eNOS protein detection. Primary human umbilical vein cordendothelial cells (HUVEC) were isolated and cultivated according tostandard procedures. Confluent cells were incubated with compounds for18 h and the effect on eNOS protein expression determined by aquantitative Western blotting procedure. After compound incubation,HUVEC were lysed in ice-cold lysis buffer containing 10 mM Tris-HCl, pH8.0, 1% SDS and protease inhibitors. The lysate was subjected to astandard denaturing polyacrylamide gel electrophoresis and blotted tonitrocellulose membranes. Using a specific primary monoclonal antibody(Transduction Laboratories, UK) and alkaline phosphatase labeledsecondary antibody (Jackson Labs), a specific eNOS protein band wasvisualized and quantified based on a chemofluorescence detection method.

The effect of the compounds of formulae I, Ia and Ib can also beinvestigated in the following animal models (animal experiments areperformed in accordance with the German animal protection law and theguidelines for the use of experimental animals as given by the Guide forthe Care and Use of Laboratory Animals of the US National Institutes ofHealth).

Animals and Treatment (Experiments B-E)

ApoE and eNOS deficient mice (C57BL/6J background, Jackson Laboratory,Bar Harbor, Me.) are used. All animals are 10 to 12 weeks of age andweigh 22 to 28 g. Three days before surgery mice are divided into 4groups (apoE control, n=10 to 12; apoE with test compounds, n=10 to 12;eNOS control, n=10 to 12; eNOS with test compounds, n=10 to 12) andreceive either a standard rodent chow (containing 4% of fat and 0.001%of cholesterol; in the following designated as placebo group) or astandard rodent chow+test compound (10 or 30 mg/kg/day p.o.).

B) Anti-Hypertensive Effect in ApoE Knockout Mice

Blood-pressure is determined in conscious mice using a computerizedtail-cuff system (Visitech Systems, Apex, N.C.). After treatment of ApoEdeficient mice and eNOS deficient mice with the test compounds the bloodpressure is compared to the results obtained with a placebo treatment.

C) Inhibition of Neointima Formation and Atherogenesis (Femoral ArteryCuff)

After 3 day treatment of ApoE deficient mice with the respectivecompound (10 mg/kg/day pressed in chow), animals are anesthetized withan intraperitoneal injection of pentobarbital (60 mg/kg) followed by anintramuscular injection of xylazin (2 mg/kg) and a cuff is placed aroundthe femoral artery as described in Moroi et al. (J Clin. Invest. 101(1998), 1225-1232). Briefly, the left femoral artery is dissected. Anon-occlusive 2.0 mm polyethylene cuff made of PE 50 tubing (innerdiameter 0.56 mm, outer diameter 0.965 mm, Becton Dickinson, MountainView, Calif.) is placed around the artery and tied in place with two 7-0sutures. The right femoral artery is isolated from the surroundingtissues but a cuff is not placed. Treatment with the respective compoundis continued for 14 days after surgery. Then the animals are sacrificed.The aorta are taken for determination of vascular eNOS expressions byquantitative western blotting. Both femoral arteries are harvested,fixed in formalin and embedded in paraffin. 20 cross sections (10 μm)are cut from the cuffed portion of the left femoral artery and from thecorresponding segment of the right artery. Sections are subjected tostandard hematoxylin and eosin staining. Morphometric analyses areperformed using an image analysis computer program (LeicaQWin, LeicaImaging Systems, Cambridge, GB). For each cross section the area of thelumen, the neointima and the media are determined. To this end, theneointima is defined as the area between the lumen and the internalelastic lamina and the media is defined as the area between the internaland the external elastic lamina. The ratio between the area of theneointima and the area of the media is expressed as the neointima/mediaratio. The results obtained in the compound group are compared to thoseobtained in the placebo group.

D) Prevention of Atherosclerotic Plaque Formation in Chronic Treatment

ApoE deficient mice are treated for 16 weeks with the respectivecompound pressed in chow and finally sacrificed. Aortas are removed fromeach mouse, fixed in formalin and embedded in paraffin. Plaque formationis measured via lipid lesions formation in the aortas (from aortic archto diaphragm) and is analyzed by oil red O staining. For quantifying theeffect of the respective compound on vascular eNOS expression thefemoral arteries are used in this experiment. The results obtained inthe compound group are compared to those obtained in the placebo group.

E) Improvement of Coronary Function in Diseased ApoE Deficient Mice

Old Male wild-type C57BL/6J mice (Charles River Wiga GmbH, Sulzfeld),and apoE deficient mice (C57BL/6J background, Jackson Laboratory, BarHarbor, Me.) of 6 month of age and weighing 28 to 36 g are used in theexperiments. Mice are divided into 3 groups (C57BL/6J, n=8; apoEcontrol, n=8; apoE with respective compound, n=8) and receive for 8weeks either a standard rodent chow (containing 4% of fat and 0.001% ofcholesterol) or a standard rodent chow+respective compound (30 mg/kg/dayp.o.). Mice are anesthetized with sodium pentobarbitone (100 mg/kgi.p.), and the hearts are rapidly excised and placed into ice-coldperfusion buffer. The aorta is cannulated and connected to a perfusionapparatus (Hugo Sachs Electronics, Freiburg, Germany) which is startedimmediately at a constant perfusion pressure of 60 mm Hg. Hearts areperfused in a retrograde fashion with modified Krebs bicarbonate buffer,equilibrated with 95% O₂ and 5% CO₂ and maintained at 37.5° C. A beveledsmall tube (PE 50) is passed through a pulmonary vein into the leftventricle and pulled through the ventricular wall, anchored in the apexby a fluted end, and connected to a tip-micromanometer (Millar 1.4French). The left atrium is cannulated through the same pulmonary veinand the heart switched to the working mode with a constant preloadpressure of 10 mm Hg and an afterload pressure of 60 mm Hg. Aorticoutflow and atrial inflow are continuously measured using ultrasonicflow probes (HSE/Transonic Systems Inc.). Coronary flow is calculated asthe difference between atrial flow and aortic flow. All hemodynamic dataare digitized at a sampling rate of 1000 Hz and recorded with a PC usingspecialized software (HEM, Notocord).

Hearts are allowed to stabilize for 30 min. All functional hemodynamicdata are measured during steady state, and during volume and pressureloading. Left ventricular function curves are constructed by varyingpre-load pressure. For acquisition of preload curves, afterload is setat 60 mm Hg and preload is adjusted in 5 mm Hg steps over a range of 5to 25 mm Hg. Hearts are allowed to stabilize at baseline conditionsbetween pressure and volume loading.

1. A method of treating a patient for a condition which responds to thestimulation of the expression of endothelial NO synthase, the methodcomprising administering to the patient a pharmaceutically effectivedose of a compound of formula I,

in which R is chosen from halogen, (C₁-C₆)-alkyl which can besubstituted by one or more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl,hydroxy, (C₁-C₆)-alkoxy which can be substituted by one or more fluorineatoms, (C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-((C₁-C₆)-alkyl)amino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro andpentafluorosulfanyl; R1 is chosen from hydrogen and (C₁-C₆)-alkyl; R2 ischosen from hydrogen and (C₁-C₆)-alkyl; R3 is chosen from Br, cyano,(C₁-C₆)-alkoxycarbonyl, —C(═NR4)-NHR5, COOH and —C(═O)—NR6R7; R4 ischosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyl-oxy,(C₁-C₁₈)-alkylcarbonyl-oxy-(C₁-C₆)-alkoxycarbonyl,(C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryloxycarbonyl, hydroxy,(C₁-C₆)-alkylcarbonyl-oxy, (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkylaminocarbonyl-oxy, di-((C₁-C₆)-alkyl)aminocarbonyl-oxy,(C₁-C₆)-alkylaminocarbonyl and di-((C₁-C₆)-alkyl)aminocarbonyl, whereinall aryl groups can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl; R5 is chosen from hydrogen, cyano, hydroxy,(C₁-C₆)-alkoxy and (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy; or R4 and R5 formtogether with the —N═C—NH— group which carries them a 4-membered to7-membered, saturated or partially unsaturated heterocyclic ring whichcan be substituted by one or more identical or different substituents R1and which, in addition to the nitrogen atoms being part of the —N═C—NH—group, can contain one or two further ring members chosen from ═N—,—NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —SO—, —SO₂— cannot be present in adjacent ring positions; R6 and R7are independently chosen from hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, —(CH₂)_(o)—(C₆-C₁₄)-aryl and —(CH₂)_(p)-heteroaryl,wherein the aryl and heteroaryl residues can be substituted by one ormore identical or different substituents chosen from halogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; or R6 and R7 formtogether with the nitrogen atom which carries them a 4-membered to7-membered, saturated, partially unsaturated or aromatic heterocyclicring which can be substituted by one or more identical or differentsubstituents R1 and which, in addition to the nitrogen atom connectingR6 and R7, can contain one or two further ring members chosen from ═N—,—NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —SO— and —SO₂— cannot be present in adjacent ring positions; n ischosen from 0, 1, 2, 3, 4 and 5; o and p are independently chosen from0, 1, 2, 3, 4 and 5; or a physiologically acceptable salt thereof. 2.The method as claimed in claim 1 wherein the condition is selected fromthe group consisting of cardiovascular diseases, stable or unstableangina pectoris, coronary heart disease, coronary artery disease,Prinzmetal angina, acute coronary syndrome, cardiac insufficiency, heartfailure, myocardial infarction, stroke, thrombosis, peripheral arteryocclusive disease, endothelial dysfunction, atherosclerosis, restenosis,endothelial damage after PTCA, hypertension, essential hypertension,pulmonary hypertension, secondary hypertension, renovascularhypertension, chronic glomerulonephritis, erectile dysfunction,ventricular arrhythmia, diabetes, diabetes complications, nephropathy,retinopathy, angiogenesis, bronchial asthma, chronic renal failure,cirrhosis of the liver, osteoporosis, restricted memory performance or arestricted ability to learn, and lowering of cardiovascular risk of apostmenopausal woman or a woman after intake of contraceptives.
 3. Themethod as claimed in claim 2 wherein the condition is selected from thegroup consisting of chronic heart failure, stable angina pectoris,coronary heart disease, hypertension, endothelial dysfunction,atherosclerosis and diabetes complications.
 4. The method as claimed inclaim 1, wherein in the compound of formula I or physiologicallyacceptable salt thereof R is chosen from halogen, (C₁-C₆)-alkyl anddi-((C₁-C₆)-alkyl)amino; R1 is hydrogen; R2 is chosen from hydrogen and(C₁-C₆)-alkyl; R3 is chosen from Br, cyano, (C₁-C₆)-alkoxycarbonyl,—C(═NR4)-NHR5, COOH and —C(═O)—NR6R7; R4 is hydrogen; R5 is hydroxy; R6is chosen from hydrogen and (C₁-C₆)-alkyl; R7 is chosen from hydrogen,(C₁-C₆)-alkyl, (C3-C₇)-cycloalkyl, phenyl and —(CH₂)_(p)-thiazolyl; orR6 and R7 form together with the nitrogen atom which carries them a4-membered to 7-membered, saturated heterocyclic ring; n is chosen from0 and 1; and p is chosen from 0 and
 1. 5. The method as claimed in claim1, wherein the compound of formula I is chosen from6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,6-(3-chloro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester, 3-methyl-6-p-tolyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester, 3-methyl-6-phenyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,6-(4-diethylamino-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid ethyl ester,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidmethyl-phenyl-amide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidamide, 6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid dimethylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidtert-butylamide,azetidin-1-yl-[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-methanone,[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-piperidin-1-yl-methanone,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiethylamide,[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-pyrrolidin-1-yl-methanone,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidthiazol-2-ylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidcyclopropylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiisopropylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidphenylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(thiazol-2-ylmethyl)-amide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile,6-(4-fluoro-phenyl)-N-hydroxy-3-methyl-imidazo[2,1-b]thiazole-2-carboxamidine,2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole, and6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole-2-carboxylic acid, or aphysiologically acceptable salt thereof.
 6. A pharmaceutical compositioncomprising an effective dose of at least one compound of formula Ia, ora physiologically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, wherein formula Ia is

in which R is chosen from halogen, (C₁-C₆)-alkyl which can besubstituted by one or more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl,hydroxy, (C₁-C₆)-alkoxy which can be substituted by one or more fluorineatoms, (C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-((C₁-C₆)-alkyl)amino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro andpentafluorosulfanyl; R1 is chosen from hydrogen and (C₁-C₆)-alkyl; R2 ischosen from hydrogen and (C₁-C₆)-alkyl; R3 is chosen from Br, cyano,—C(═NR4)-NHR5 and —C(═O)—NR6R7; R4 is chosen from hydrogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkoxycarbonyl-oxy,(C₁-C₁₈)-alkylcarbonyl-oxy-(C₁-C₆)-alkoxycarbonyl,(C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryloxycarbonyl, hydroxy,(C₁-C₆)-alkylcarbonyl-oxy, (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkylaminocarbonyl-oxy, di-((C₁-C₆)-alkyl)aminocarbonyl-oxy,(C₁-C₆)-alkylaminocarbonyl and di-((C₁-C₆)-alkyl)aminocarbonyl, whereinall aryl groups can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl; R5 is chosen from hydrogen, cyano, hydroxy,(C₁-C₆)-alkoxy and (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy; or R4 and R5 formtogether with the —N═C—NH— group which carries them a 4-membered to7-membered, saturated or partially unsaturated heterocyclic ring whichcan be substituted by one or more identical or different substituents R1and which, in addition to the nitrogen atoms being part of the —N═C—NH—group, can contain one or two further ring members chosen from ═N—,—NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —SO—, —SO₂— cannot be present in adjacent ring positions; R6 and R7are independently chosen from hydrogen and (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, —(CH₂)_(o)—(C₆-C₁₄)-aryl and —(CH₂)_(p)-heteroaryl,wherein the aryl and heteroaryl residues can be substituted by one ormore identical or different substituents chosen from halogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; or R6 and R7 formtogether with the nitrogen atom which carries them a 4-membered to7-membered, saturated, partially unsaturated or aromatic heterocyclicring which can be substituted by one or more identical or differentsubstituents R1 and which, in addition to the nitrogen atom connectingR6 and R7, can contain one or two further ring members chosen from ═N—,—NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —SO— and —SO₂— cannot be present in adjacent ring positions; n ischosen from 0, 1, 2, 3, 4 and 5; o and p are independently chosen from0, 1, 2, 3, 4 and 5, or a physiologically acceptable salt thereof. 7.The pharmaceutical composition as claimed in claim 6, wherein in thecompound of formula Ia or physiologically acceptable salt thereof R ischosen from halogen; R1 is hydrogen; R2 is chosen from (C₁-C₆)-alkyl; R3is chosen from Br, cyano, —C(═NR4)-NHR5 and —C(═O)—NR6R7; R4 ishydrogen; R5 is hydroxy; R6 is chosen from hydrogen and (C₁-C₆)-alkyl;R7 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, phenyland —(CH₂)_(p)-thiazolyl; or R6 and R7 form together with the nitrogenatom which carries them a 4-membered to 7-membered, saturatedheterocyclic ring; n is 1; p is chosen from 0 and
 1. 8. A pharmaceuticalcomposition comprising an effective dose of at least one compound chosenfrom 6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid ethyl ester,6-(3-chloro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester, 3-methyl-6-p-tolyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,6-(4-diethylamino-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid ethyl ester,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidmethyl-phenyl-amide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidamide, 6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid dimethylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidtert-butylamide,azetidin-1-yl-[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-methanone,[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-piperidin-1-yl-methanone,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiethylamide,[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-pyrrolidin-1-yl-methanone,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidthiazol-2-ylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidcyclopropylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiisopropylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidphenylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(thiazol-2-ylmethyl)-amide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile,6-(4-fluoro-phenyl)-N-hydroxy-3-methyl-imidazo[2,1-b]thiazole-2-carboxamidine,2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole, and6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole-2-carboxylic acid, or aphysiologically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 9. A compound of formula Ib

in which R is chosen from halogen, (C₁-C₆)-alkyl which can besubstituted by one or more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl,hydroxy, (C₁-C₆)-alkoxy which can be substituted by one or more fluorineatoms, (C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-((C₁-C₆)-alkyl)amino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro andpentafluorosulfanyl; R1 is chosen from hydrogen and (C₁-C₆)-alkyl; R2 ischosen from hydrogen and (C₁-C₆)-alkyl; R3 is chosen from Br, cyano and—C(═NR4)-NHR5; R4 is chosen from hydrogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkoxycarbonyl-oxy,(C₁-C₁₈)-alkylcarbonyl-oxy-(C₁-C₆)-alkoxycarbonyl,(C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryloxycarbonyl, hydroxy,(C₁-C₆)-alkylcarbonyl-oxy, (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkylaminocarbonyl-oxy, di-((C₁-C₆)-alkyl)aminocarbonyl-oxy,(C₁-C₆)-alkylaminocarbonyl and di-((C₁-C₆)-alkyl)aminocarbonyl, whereinall aryl groups can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl; R5 is chosen from hydrogen, cyano, hydroxy,(C₁-C₆)-alkoxy and (C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy; or R4 and R5 formtogether with the —N═C—NH— group which carries them a 4-membered to7-membered, saturated or partially unsaturated heterocyclic ring whichcan be substituted by one or more identical or different substituents R1and which, in addition to the nitrogen atoms being part of the —N═C—NH—group, can contain one or two further ring members chosen from ═N—,—NR1-, —C(═O)—, —O—, —S—, —SO— and —SO₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —SO— and —SO₂— cannot be present in adjacent ring positions; n ischosen from 0, 1, 2, 3, 4 and 5; or a physiologically acceptable saltthereof.
 10. A compound of formula Ib as claimed in claim 9, in which Ris chosen from halogen; R1 is hydrogen; R2 is chosen from (C₁-C₆)-alkyl;R3 is chosen from Br, cyano and —C(═NR4)-NHR5; R4 is hydrogen; R5 ishydroxy; n is 1; or a physiologically acceptable salt thereof.
 11. Acompound chosen from6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,6-(3-chloro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester, 3-methyl-6-p-tolyl-imidazo[2,1-b]thiazole-2-carboxylic acidethyl ester,6-(4-diethylamino-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid ethyl ester,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidmethyl-phenyl-amide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidamide, 6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylicacid dimethylamide,azetidin-1-yl-[6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazol-2-yl]-methanone,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiethylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidthiazol-2-ylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acidcyclopropylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic aciddiisopropylamide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid(thiazol-2-ylmethyl)-amide,6-(4-fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile,6-(4-fluoro-phenyl)-N-hydroxy-3-methyl-imidazo[2,1-b]thiazole-2-carboxamidine,2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole, and6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole-2-carboxylic acid, or aphysiologically acceptable salt thereof.
 12. A pharmaceuticalcomposition, comprising an effective dose of at least one compound asclaimed in claim 9, or a physiologically acceptable salt thereof, and apharmaceutically acceptable carrier.